Plasmodium falciparum causes the most severe form of malaria disease and is the major cause of infection-related mortalities in the world. Due to increasing in P. falciparum resistance to the first-line antimalarial drugs, an effective vaccine for the control and elimination of malaria infection is urgent. Because the pathogenesis of malaria disease results from blood-stage infection, and all of the symptoms and clinical illness of malaria occur during this stage, there is a strong rationale to develop vaccine against this stage. In the present study, different structural-vaccinology and immuno informatics tools were applied to design an effective antibody-inducing multi-epitope vaccine against the blood-stage of P. falciparum. The designed multi-epitope vaccine was composed of three main parts including B cell epitopes, T helper (Th) cell epitopes, and two adjuvant motives (HP91 and RS09), which were linked to each other via proper linkers. B cell and T cell epitopes were derived from four protective antigens expressed on the surface of merozoites, which are critical to invade the erythrocytes. HP91 and RS09 adjuvants and Th cell epitopes were used to induce, enhance and direct the best form of humoral immune-response against P. falciparum surface merozoite antigens. The vaccine construct was modeled, and after model quality evaluation and refinement by different software, the high-quality 3D-structure model of the vaccine was achieved. Analysis of immunological and physicochemical features of the vaccine showed acceptable results. We believe that this multi-epitope vaccine can be effective for preventing malaria disease caused by P. falciparum.The COVID-19 pandemic has dramatically changed the practice medicine on a global scale during the year 2020. With fewer patients presenting to hospitals with the diagnosis of STEMI, healthcare workers are wondering what is causing this decline. This piece presents data from two medical centers and addresses several possible causes to explain this phenomenon. It was found that there was a statistically significant decrease from January to March 2020 in number of presenting STEMI diagnoses.Under conditions of oxidative stress, reactive oxygen species (ROS) continuously assault the structure of DNA resulting in oxidation and fragmentation of the nucleobases. When the nucleobase structure is altered, its base-pairing properties may also be altered, promoting mutations. Consequently, oxidative DNA damage is a major source of the mutation load that gives rise to numerous human maladies, including cancer. Base excision repair (BER) is the primary pathway tasked with removing and replacing mutagenic DNA base damage. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central enzyme with AP-endonuclease and 3' to 5' exonuclease functions during BER, and therefore is key to maintenance of genome stability. Polymorphisms, or SNPs, in the gene encoding APE1 (APEX1) have been identified among specific human populations and result in variants of APE1 with modified function. These defects in APE1 potentially result in impaired DNA repair capabilities and consequently an increased risk of disease for individuals within these populations. In the present study, we determined the X-ray crystal structures of three prevalent disease-associated APE1 SNPs (D148E, L104R, and R237C). Each APE1 SNP results in unique localized changes in protein structure, including protein dynamics and DNA binding contacts. Combined with comprehensive biochemical characterization, including pre-steady-state kinetic and DNA binding analyses, variant APE1DNA complex structures with both AP-endonuclease and exonuclease substrates were analyzed to elucidate how these SNPs might perturb the two major repair functions employed by APE1 during BER.Purpose Based on recent advances in the management of patients with sentinel node (SN)-positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM). Methods The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation. Results The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. Inflammation inhibitor The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of less then 25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance. Conclusions The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making.Background Data on spectrum and grade of immune-related adverse events (irAEs) in long-term responders to immune checkpoint inhibitors (ICIs) are lacking. Methods We performed a retrospective multicenter study to characterized irAEs occurring after a 12-months minimum treatment period with PD-(L)1 ICIs in patients with advanced cancer. IrAEs were categorized into 'early' (≤12 months) and 'late' (>12 months). Results From September 2013 to October 2019, 436 consecutive patients were evaluated. Two hundred twenty-three experienced any grade early-irAEs (51.1%), whereas 132 experienced any grade late-irAEs (30.3%) (p less then 0.0001). Among the latter, 29 (22%) experienced a recurrence of an early-irAEs, whereas 103 (78%) experienced de novo late-irAEs involving different system/organ. Among patients with late-irAEs, 21 experienced GIII/GIV irAEs (4.8%). Median time to onset of early-irAEs was 3.4 months (95% confidence interval [CI] 2.8-4.2), whereas the median time to onset of late-irAEs was 16.6 months (95% CI 15.